tbuckley/cabot-search huggingface dataset:
Abstract 13516: Natural History, Penotypes and Clinical Outcomes in Desmin Related Arrhythmogenic Cardiomyopathy
Authors: Francisco Jose Bermudez-Jimenez, Alexandros Protonotarios, Alessandra Rampazzo, Esther Zorio, Andreas Brodehl, Miguel Ángel Arias, Juan Fernández Armenta, Rosa Macías-Ruiz, Pablo Garcia-Pavia, Juan Ramón Gimeno, Luis R Lopes, Perry M Elliott, Juan Jimenez-Jaimez
Journal: Circulation (2022)

Background: Mutations in DES gene, encoding the intermediate filament desmin, have been related to arrhythmogenic cardiomyopathy (AC). Our aim is to describe the clinical phenotype, natural history and outcomes in a multicentric international cohort of desmin-related AC patients. Methods: Probands and relatives (85 individuals from 11 families (45% men; mean age 35 [IQR] 23.5-53.5 years old)) carrying a DES mutation from 8 European centers were included. Clinical, electrocardiographical and advanced cardiac imaging data were retrospectively collected and analysed. DES mutations were transfected into cell lines and analyzed by confocal microscopy. Results: Disease penetrance in individuals ≥30 years was 80.8% and 71.4% in individuals &lt;30 years; A left dominant or biventricular form of AC was the main clinical phenotype (69 cases, 81 %). More than half of the patients presented low voltage on the ECG, the mean LVEF was 48.9±16% and the mean RVEF was 53.8±10%. A high prevalence of patients with magnetic resonance imaging (n=30) presented fibrosis (65,2%), with a particular circunferencial (“ring-like”) pattern in 46.4% (Figure A). After a median follow-up of 6 years, 24.7% died (mean age 62[33-76]) (Figure B) and 8.2% suffered appropriate shocks (age 47[31-69.5]) or SD (age 33 [24.5-49]). Finally, there were 6 heart transplants (age 54 [33-68]). A LVEF&lt;50% and male sex were associated with major cardiovascular events. In three DES mutations (E401D, L115E and R415Q) desmin aggreggates were observed (Figure C) Conclusions AC due to DES mutations have a high clinical penetrance as a left dominant or biventricular form of the disease, with an early onset and a high burden of cardiovascular events. A LV “ring-like” LGE pattern was particularly common. Male sex or mildly depressed LVEF were predictors for SD. DES mutation may be pathogenic by causing desmin aggregates. A) Annular pattern of fibrosis B) Carriers free-of-events survival curve. C) Desmin aggregates
Abstract 13259: Genome Sequencing in Pediatric Patients With Pulmonary Vein Stenosis
Authors: Cherith Somerville, Roozbeh Manshaei, Qiliang Ding, Kelsey Kalbfleisch, Raymond Kim, Rebekah Jobling, Rachel Vanderlaan
Journal: Circulation (2022)

Introduction: Pulmonary vein stenosis (PVS) is a rare and progressive disease of the vasculature, characterized by neointimal proliferation and is frequently lethal in pediatric patients. PVS is clinically heterogeneous, and its etiology remains unknown. Insight into the genetic basis of PVS can help to direct treatment interventions and improve clinical outcomes. Objectives: To examine the genetic mechanisms underlying PVS and to compare the genetic architecture in patients with severe disease to patients with disease stabilization. Methods: We performed genome sequencing in a cohort of 18 pediatric patients with PVS. The genomic data was analyzed for clinically reportable variants and biologically plausible candidates. We used a statistical overrepresentation test to investigate the overrepresentation of gene ontology (GO) terms in patients with aggressive disease compared with stabilized patients. Results: Seven patients (38.9%) had aggressive disease, resulting in death or lung transplant, 16 patients (88.9%) had concomitant congenital heart disease, and 11 patients (61.1%) had extracardiac anomalies. In two patients (11.1%) with a syndromic presentation, we identified Pathogenic/Likely Pathogenic variants in three genes: ANKRD11, associated with KBG syndrome, FOXP1 , and DYNC1H1 , associated with intellectual developmental disorders. In search of novel candidate genes, we identified de novo variants in PAK4 , AMBRA1 , and ANKRD50 , involved in cytoskeletal remodeling, mTOR-regulated autophagy, and protein trafficking, respectively. In patients with severe PVS, we found an overrepresentation of rare (minor allele frequency &lt;0.15%) coding variants in genes involved in blood vessel morphogenesis (FDR &lt;0.05), protein phosphorylation (FDR &lt;0.05), dynein intermediate chain binding (FDR &lt;0.05), and ATP binding (FDR &lt;0.05). No GO terms were overrepresented in the patients with stabilized disease. Conclusions: This exploratory cohort of patients with PVS provides further insight into the genetic contributions to PVS. These results suggest distinct genetic landscapes between progressive and stabilized disease. Genetic testing in larger cohorts is needed to further define the molecular pathology of pediatric PVS.
Abstract 13305: Impact of Small Cajal-Body Associated RNAs in IPSC-Derived Cardiomyocytes From Progeria and Noonan Patients
Authors: Vinoth Sigamani, Selene G Perales, Saiprahalad Mani, SHEEJA RAJASINGH, Rajasingh Johnson
Journal: Circulation (2022)

Introduction: Progeria and Noonan syndrome are major genetic disorders that impact the cardiovascular system and lead to congenital heart defects in children. The small Cajal body-associated RNAs (scaRNAs) are a class of H/ACA box non-coding RNAs, which play an important role in the biochemical modification of spliceosomal RNAs and contribute to alternative splicing and maturation of mRNAs. In this study, we aim to elucidate the role of scaRNAs during cardiac differentiation and its effect in Progeria and Noonan Patients-derived induced pluripotent stem cell-derived cardiomyocytes (iCMC). Hypothesis: We hypothesize that scaRNAs have a significant role in cardiac development and are associated with cardiovascular development in disease conditions. Methods and Results: To elucidate the role of scaRNAs in Noonan and Progeria patients during cardiomyogenesis, we differentiated iCMCs from iPSCs generated from Noonan (c.1654A&gt;G) and Progeria (c.1824 C&gt;T) patients. The differential expression of scaRNAs was performed by qRT-PCR and the result shows that scaRNA6, scaRNA11, scaRNA14 scaRNA20, and scaRNA28 were significantly reduced in Noonan and Progeria patients iCMC compared to normal skin fibroblast (SF)-derived iCMCs and Urinary epithelial cells (UE)-derived iCMC (Fig.1). The mRNA expression of the cardiac-specific gene in Progeria and Noonan patient-derived iCMC was significantly reduced when compared with normal iCMC. Furthermore, the scaRNA overexpressed normal iCMCs (scaRNA20-OE-iCMCs) showed significantly increased cardiac-specific mRNA and protein expressions when compared with control iCMC (Figs.2 &amp; 3) . Conclusion: Our finding indicates that scaRNAs have major impacts on Noonan and Progeria patient-derived iCMC. Targeting the scaRNAs will have efficient therapeutic potential for Noonan and Progeria patients.
Abstract 13368: Effect of Peripheral Endothelial Function Assessment in Improving the Risk Stratification of Major Cardiovascular Events Beyond CHA2DS2-Vasc
Authors: Nazanin Rajai, Takumi Toya, Jaskanwal D Sara, Francisco Lopez-Jimenez, Lilach O Lerman, Amir Lerman
Journal: Circulation (2022)

Introduction: Peripheral microvascular endothelial dysfunction (PMED) is a marker and precursor of atherosclerosis and is associated with an increased risk of cardiovascular events. The present study aims to identify the best cut-off value of PMED, assessed by the reactive hyperemia index, in predicting major adverse cardiovascular events (MACE). Additionally, we investigate whether integrating PMED to CHA2DS2-Vasc score improves the predicting accuracy of cardiovascular disease. Methods: this is a retrospective study of patients who underwent reactive hyperemia peripheral arterial tonometry (PAT). The optimal cut-off value of reactive hyperemia index associated with MACE was calculated using the area under the receiver-operating curve and the maximum Youden index. Traditional cardiovascular risk factors such as age, sex, congestive heart failure, hypertension, diabetes, stroke, vascular disease were determined to calculate the CHA2DS2-VASc score. MACE was defined as myocardial infarction, heart failure hospitalization, and cerebrovascular events. Results: 1,690 patients were enrolled (average age 51.1±13.9, 64.1% female). The optimal cut-off value of the reactive hyperemia index was 2.0 in the overall population and females and 2.17 in males. The risk of MACE during 10 (Interquartile range: 4,16) years of follow-up was 15.3%. Multivariable logistic regression revealed that PMED as an independent predictor of MACE (PMED: OR, 3.6, 95% CI, 2.6-4.9, p&lt;0.001) (Table1). Furthermore, integrating PMED to CHA2DS2-VASc significantly improved the predictive accuracy (area under the curve, 0.747 vs. 0.708, p&lt;0.001). Conclusion: PMED is a strong predictor of cardiovascular events. Non-invasive assessment of peripheral endothelial function may be useful in early detection and improving the stratification of high-risk patients for cardiovascular events.
Abstract 13688: Low-Affinity Insulin-Like Growth Factor Binding Protein 7 and Its Association With Pulmonary Arterial Hypertension Severity and Survival
Authors: Guillermo Torres-Viera, Andrew Lancaster, Jun Yang, Megan Griffiths, Stephanie Brandal, Rachel L Damico, Allen D Everett, Dunbar D Ivy, Eric Austin, Catherine Simpson, Dhananjay Vaidya, Bill Nichols
Journal: Circulation (2022)

Introduction: Insulin like growth factor binding proteins (IGFBPs) are a family of growth factor modifiers, some of which are known to be independently associated with PAH survival. IGFBP7 is a unique low-affinity IGFBP that, independent of IGF, stimulates prostacyclin production. Hypothesis: Elevated IGFBP7 is associated with worse disease severity and survival in PAH. Methods: Using enzyme-linked immunosorbent assays (ELISA), we evaluated serum IGFBP7 in a multicenter PAH cohort, the NHLBI PAHBiobank (N=2583), and healthy controls (N=99). Hemodynamic and functional measures were used to assess IGFBP7’s association to PAH severity and survival. Kruskal Wallis was used for comparison and Spearman’s rank correlation for correlations. Linear and logistic regressions performed for associations. IGFBP7 was dichotomized at the median and analyzed by Kaplan-Meier survival and Cox proportional Hazard regression. Results: Serum IGFBP7 levels were significantly elevated in patients with PAH compared to controls. After adjustment, logarithmic increases in IGFBP7 were associated with a 38 meter shorter six-minute walk distance (6MWD; -37.7, 95%CI -54 to -21, p=&lt;0.001), a higher mean right atrial pressure (2.18mmHg, 95%CI 1.51-2.89, p&lt;0.001) and a higher REVEAL risk score (1.10, 95%CI 0.88-1.33, p &lt;0.001). Logarithmic increases in IGFBP7 were also associated with a two-times higher likelihood of having PAH associated with Portopulmonary disease (2.39, 95%CI 1.95-2.84, p&lt;0.001). Kaplan Meier analysis demonstrated significant survival effects of IGFBP7 above the median (see Figure 1) and an adjusted (age, sex, functional class, and 6MWD) Cox proportional hazards model (HR 3.1, 95% CI 2.2-4.4, p&lt;0.001). Conclusions: Higher circulating IGFBP7 levels were significantly associated with worse PAH severity and decreased survival. Given its role of as a prostacyclin stimulant, IGFBP7 may also serve as a therapeutic target for disease modulation.
Abstract 13744: The Association of Pre-Pregnancy Obesity on Postpartum Blood Pressure in Preeclampsia
Authors: Eliza A Miller, Anum A Minhas, Alborz Soleimani-Fard, Arthur J Vaught, Allison G Hays, Erin D Michos, Steven P Schulman, Chiadi E Ndumele
Journal: Circulation (2022)

Background: Women with preeclampsia have elevated risk of long-term cardiovascular disease, in part mediated by postpartum hypertension. Little is known about the association of pre-pregnancy obesity with postpartum blood pressure. Hypothesis: We hypothesized that women with pre-pregnancy obesity and preeclampsia will have higher postpartum blood pressure compared to women without preeclampsia. Methods: We included women with preeclampsia followed between 2021-2022 at a tertiary care academic center. An equal number of women without preeclampsia were then included, matched for body mass index (BMI). Pre-pregnancy weight (exposure variable) was categorized according to BMI (in kg/m 2 ) at the initial antenatal visit as follows: normal weight (&lt;25), overweight (25-&lt;30), class I obesity (30-&lt;35) and class II+ obesity ( &gt; 35 kg/m 2 ). MAP from the 6 week postpartum visit was the outcome variable. Adjusted linear regression was performed for the association of BMI category with MAP, stratified by preeclampsia status. Interaction between BMI category and preeclampsia on the outcome of MAP was tested in the fully adjusted model. Results: Among 426 women, 247 had preeclampsia. Mean age was 31 + 6 and 32 + 5 years for women with and without preeclampsia, respectively. 54% of women with preeclampsia and 43% without identified as Black. Chronic hypertension was present in 30% vs 11% of women with vs without preeclampsia. Among women with preeclampsia, obesity class II/III was associated with higher postpartum MAP than normal weight (Table). This association was not seen in women without preeclampsia (p-value interaction = 0.004). Conclusion: Higher pre-pregnancy BMI is associated with greater postpartum MAP in women with preeclampsia, but not in women without preeclampsia. These findings underscore the importance of reducing the burden of pre-pregnancy obesity in populations at risk for preeclampsia, to prevent long-term adverse cardiovascular outcomes after pregnancy.
Abstract 13214: Circulating Progenitor Cells Are Associated With Bioprosthetic Aortic Valve Deterioration
Authors: Yoshihisa Kanaji, Ilke Ozcan, Takumi Toya, Rajiv Gulati, Melissa Young, Tsunekazu Kakuta, Lilach O Lerman, Amir Lerman
Journal: Circulation (2022)

Introduction: Mechanisms underlying bioprosthetic valve deterioration (BVD) are multifactorial and incompletely elucidated. Reparative circulating progenitor cells (CPCs), and conversely calcification-associated osteocalcin expressing CPCs (CPC-OCN), have been linked to native aortic valve deterioration. However, their role in BVD remains elusive. This study sought to evaluate the contribution of different subpopulations of CPCs in BVD. Methods: This prospective study enrolled 121 patients who had peripheral blood mononuclear cells (PBMC) isolated prior to bioprosthetic aortic valve replacement (surgical 104, transcatheter 17) and had an echocardiographic follow-up ≥2 years after the procedure. Using flow cytometry, fresh PBMC were analyzed for the surface markers CD34, CD133, and osteocalcin (OCN). BVD was evaluated by hemodynamic valve deterioration (HVD) using echocardiography, which was defined as an elevated mean transprosthetic gradient ≥30mmHg and/or at least moderate intraprosthetic regurgitation. Multivariable models were constructed to evaluate the association of each subpopulation of CPCs and other clinical characteristics with HVD. Results: Sixteen patients (13.2%) developed HVD during follow-up for a median of 5.9 years. Patients with HVD showed significantly lower levels of reparative CD34 + CD133 + cells and higher levels of OCN + cells than those without HVD (CD34 + CD133 + cells: 125 [80, 210] vs 270 [130, 420], P=0.002; OCN + cells: 3060 [523, 5528] vs 670 [180, 1930], P=0.005 respectively). Decreased level of CD34 + CD133 + cells was a significant predictor of HVD. Conclusions: Circulating levels of CD34 + CD133 + cells and OCN + cells were significantly associated with the subsequent occurrence of HVD in patients undergoing bioprosthetic aortic valve replacement. CPCs might play a vital role in the mechanism, risk stratification and a potential therapeutic target for patients with bioprosthetic valve deterioration.
Abstract 13723: Uric Acid and Treatment With Empagliflozin in Heart Failure With Preserved Ejection Fraction: The EMPEROR-Preserved Trial
Authors: Wolfram Doehner
Journal: Circulation (2022)

Background: The sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin reduces CV death and hospitalization for HF (HHF) in patients with HF with preserved ejection fraction (HFpEF). Empagliflozin reduces serum uric acid (SUA), but the relevance of this effect in HFpEF is unclear. Methods: This post-hoc analysis of the EMPEROR-Preserved trial assessed the association between SUA and the composite primary outcome of CV death or hospitalization for worsening HF, its components and all-cause mortality (ACM) in 5,924 patients with HFpEF (98.9% of study cohort). We investigated effects of empagliflozin on SUA levels and hyperuricemic events (acute gout, gouty arthritis or initiation of anti-gout therapy), and on outcomes in relation to baseline SUA and the change in SUA levels Results: Hyperuricemia was prevalent in 49% of patients (male: 42%, female: 57%). Elevated SUA (highest tertile, mean SUA 8.8±1.4mg/dL) was associated with severity of HF and higher risk of HHF (first HHF: HR 1.42 [95%CI 1.08-1.86], recurrent HHF: HR 1.69 [95%CI 1.23-2.32], in comparison with the lowest tertile within the placebo group, both p&lt;0.01). Elevated SUA was not associated with increased CV death and ACM. Empagliflozin reduced SUA at 4 weeks (vs. placebo: -1.0±0.03mg/dL, p&lt;0.0001) and SUA remained lower throughout follow up. Empagliflozin reduced events of clinically relevant hyperuricemia by 38% (HR 0.62 [95%CI 0.51-0.76], p&lt;0.0001). The benefit of empagliflozin on the primary endpoint was independent of baseline SUA (HR 0.79 [95%CI 0.69-0.90], p=0.0007) and absolute change in SUA at 4 weeks (HR 0.87 [95%CI 0.75-1.01, p=0.07] landmark analysis). The benefit of empagliflozin versus placebo on the rate of decline of eGFR and time to first renal composite outcome was consistent across SUA tertiles (p for interaction 0.92 and 0.89, respectively) Conclusion: Hyperuricemia is common in HFpEF and is an independent predictor of disease severity and increased risk of hospitalization. Empagliflozin induced a rapid, sustained reduction of SUA levels and clinical events related to hyperuricemia. The benefit of empagliflozin on the primary outcome in HFpEF was observed independently of SUA.
Abstract 13594: A Decade Trend, Sex, Racial and Economic Disparities in Acute Myocardial Infarction Hospitalizations in the United States
Authors: Jeremiah Bello, Adewale Adedoyin, Muhammad Khawar Sana, Funmilola Babalola, Abdultawab Shaka, Tomilola I Olakunde, IRIAGBONSE ASEMOTA, Hafeez Shaka
Journal: Circulation (2022)

Introduction: Reports have shown socioeconomic healthcare disparities among patients with cardiovascular diseases. We studied the trends in AMI hospitalization burden and outcomes over a decade with a focus on disparities in outcomes. This would provide epidemiologic data to assess the impact of current guidelines and recommendations on the general population. Methods: This was a trend study of the National Inpatient database from 2010 to 2019. We searched for AMI as the reason for hospitalization using the ICD codes. We estimated trends, inpatient mortality, mean length of hospital stay (LOS) and mean total hospital charges (THC) over the period. We performed a stratified analysis in categories: sex (male and female), race (Caucasians, Blacks, Hispanics), and median household income for patient's zip code (low-income quartile [LIQ] vs high-income quartile [HIQ]) to assess disparities in outcomes. Multivariable regression analysis adjusted for age and sex was used to obtain trend statistics on outcomes. Results: There were about 6,158,738 hospitalizations for AMI over the study period with females making up 38.2%. Yearly hospitalizations increased from 1,851 - 1,983 per 100,000 adult hospitalizations from 2010 to 2019 (p&lt;0.001). There was a significant increase in hospitalizations among men from 60.4% in 2010 to 63.4% in 2019 (p&lt;0.001). The proportion of AMI increased by 37% in Hispanics, 15% in Blacks, and 8% in Caucasians. The LIQ patients had a 6.2% increase while the HIQ had a 7.0% decrease in AMI hospitalizations. The mortality rate over the decade was 4.9%. Females had a mortality rate of 5.6% compared to 4.5% in Males. The LIQ average mortality was 5.0% compared to 4.9 in the HIQ. There was a significant decrease in the overall mortality from 5.3% in 2010 to 4.5% in 2019 (p&lt;0.001). The mortality in females decreased by 20.3% (p&lt;0.001) compared to 11.5% in males (p&lt;0.001). Adjusted for inflation, there was a 41.8% increase in the THC over the study period. Conclusion: Hospitalization incidence for AMI appears to be rising among males, Hispanics, and LIQ patients. Information from this study brings awareness to ongoing disparities in AMI hospitalizations. We recommend multidisciplinary and sustained efforts to eliminate socioeconomic disparities in healthcare
Abstract 13319: Cryoaballoon Ablation in Patients With Atrial Fibrillation and Heart Failure - Insights From Ongoing POLAR-HF Trial
Authors: Andreas A Boehmer, Moritz Rothe, Elena Nussbaum, Christina M Soether, Celine Zezyk, Bianca C Dobre, Bernhard M Kaess, Joachim R Ehrlich
Journal: Circulation (2022)

Background Atrial Fibrillation (AF) and heart failure (HF) often co-exist and increase cardiovascular mortality. Radiofrequency ablation is safe and effective in patients with AF and HF. There is evidence for a reduction in mortality in treated patients (CASTLE, NEJM 2019), and the European Society of Cardiology recommends catheter ablation (class 1A), particularly in patients with tachycardiomyopathy. However, there is no large-scale prospective study evaluating efficacy and safety of cryoballoon pulmonary vein isolation (cryoPVI) in patients with AF and HF. Objective Prospective comparison of cryoPVI in patients with and without HF (defined as LVEF ≤ 40%) regarding efficacy and safety. Methods POLAR-HF trial is an investigator-initiated, single-center, prospective, non-inferiority, interventional study. Follow-up was performed at 3, 6 and 12, 18 and 24 months after ablation. Endpoints were: symptomatic AF recurrence for efficacy and bleeding, stroke or death for safety. Periprocedural parameters were observed. Results: We analyzed 668 consecutive patients who underwent cryoPVI. Of these 581 had normal LVEF (age 69±10 years, CHA2DS2-VASc Score 2.7±1.5, 54% male) while 87 patients (13%) suffered from HF (age 70±10 years, CHA2DS2-VASc Score 3.3±1.4, 70% male). After 24 months primary efficacy endpoint occurrence was similar in normal LVEF and HF group (34.1 % vs. 35.6%, P=0.66, Figure). Safety endpoint occurred in form of pericardial effusion or transient phrenic nerve injury in six patients with normal LVEF (1.2%) and none in HF group. No deaths or strokes were observed in either group. Conclusion The interim results of the POLAR-HF study suggest that cryoPVI is a safe and effective ablation method for patients with atrial fibrillation and heart failure.